Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy.
Pauletti Alberto,Terrone Gaetano,Shekh-Ahmad Tawfeeq,Salamone Alessia,Ravizza Teresa,Rizzi Massimo,Pastore Anna,Pascente Rosaria,Liang Li-Ping,Villa Bianca R,Balosso Silvia,Abramov Andrey Y,van Vliet Erwin A,Del Giudice Ennio,Aronica Eleonora,Patel Manisha,Walker Matthew C,Vezzani Annamaria
Brain : a journal of neurology
Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.
The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis.
Neuroinflammation is the coordinated response of the central nervous system (CNS) to threats to its integrity posed by a variety of conditions, including autoimmunity, pathogens and trauma. Activated astrocytes, in concert with other cellular elements of the CNS and immune system, are important players in the modulation of the neuroinflammatory response. During neurological disease, they produce and respond to cellular signals that often lead to dichotomous processes, which can promote further damage or contribute to repair. This occurs also in multiple sclerosis (MS), where astrocytes are now recognized as key components of its immunopathology. Evidence supporting this role has emerged not only from studies in MS patients, but also from animal models, among which the experimental autoimmune encephalomyelitis (EAE) model has proved especially instrumental. Based on this premise, the purpose of the present review is to summarize the current knowledge of astrocyte behavior in MS and EAE. Following a brief description of the pathological characteristics of the two diseases and the main functional roles of astrocytes in CNS physiology, we will delve into the specific responses of this cell population, analyzing MS and EAE in parallel. We will define the temporal and anatomical profile of astroglial activation, then focus on key processes they participate in. These include: (1) production and response to soluble mediators (e.g., cytokines and chemokines), (2) regulation of oxidative stress, and (3) maintenance of BBB integrity and function. Finally, we will review the state of the art on the available methods to measure astroglial activation in vivo in MS patients, and how this could be exploited to optimize diagnosis, prognosis and treatment decisions. Ultimately, we believe that integrating the knowledge obtained from studies in MS and EAE may help not only better understand the pathophysiology of MS, but also uncover new signals to be targeted for therapeutic intervention.
Cien Años de Microglía: Milestones in a Century of Microglial Research.
Sierra Amanda,Paolicelli Rosa C,Kettenmann Helmut
Trends in neurosciences
The year 2019 marks the 100-year anniversary of the discovery of microglia by Pío del Río-Hortega. We will recount the state of neuroscience research at the beginning of the 20th century and the heated scientific dispute regarding microglial identity. We will then walk through some of the milestones of microglial research in the decades since then. In the last 20 years, the field has grown exponentially. Researchers have shown that microglia are unlike any other resident macrophages: they have a unique origin and distinguishing features. Microglia are extraordinarily motile cells and constantly survey their environment, interacting with neurons, astrocytes, oligodendrocytes, neural stem cells, and infiltrating immune cells. We finally highlight some open questions for future research regarding microglia's identity, population dynamics, and dual (beneficial and detrimental) role in pathology.
Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain.
Van Steenwinckel Juliette,Schang Anne-Laure,Krishnan Michelle L,Degos Vincent,Delahaye-Duriez Andrée,Bokobza Cindy,Csaba Zsolt,Verdonk Franck,Montané Amélie,Sigaut Stéphanie,Hennebert Olivier,Lebon Sophie,Schwendimann Leslie,Le Charpentier Tifenn,Hassan-Abdi Rahma,Ball Gareth,Aljabar Paul,Saxena Alka,Holloway Rebecca K,Birchmeier Walter,Baud Olivier,Rowitch David,Miron Veronique,Chretien Fabrice,Leconte Claire,Besson Valérie C,Petretto Enrico G,Edwards A David,Hagberg Henrik,Soussi-Yanicostas Nadia,Fleiss Bobbi,Gressens Pierre
Brain : a journal of neurology
Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/β-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.
Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration.
Joshi Amit U,Minhas Paras S,Liddelow Shane A,Haileselassie Bereketeab,Andreasson Katrin I,Dorn Gerald W,Mochly-Rosen Daria
In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.
The role of astroglia in Alzheimer's disease: pathophysiology and clinical implications.
Arranz Amaia M,De Strooper Bart
The Lancet. Neurology
BACKGROUND:Astrocytes, also called astroglia, maintain homoeostasis of the brain by providing trophic and metabolic support to neurons. They recycle neurotransmitters, stimulate synaptogenesis and synaptic neurotransmission, form part of the blood-brain barrier, and regulate regional blood flow. Although astrocytes have been known to display morphological alterations in Alzheimer's disease for more than a century, research has remained neurocentric. Emerging evidence suggests that these morphological changes reflect functional alterations that affect disease. RECENT DEVELOPMENTS:Genetic studies indicate that most of the risk of developing late onset Alzheimer's disease, the most common form of the disease, affecting patients aged 65 years and older, is associated with genes (ie, APOE, APOJ, and SORL) that are mainly expressed by glial cells (ie, astrocytes, microglia, and oligodendrocytes). This insight has moved the focus of research away from neurons and towards glial cells and neuroinflammation. Molecular studies in rodent models suggest a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease; however, these models might insufficiently mimic the human disease, because rodent astrocytes differ considerably in morphology, functionality, and gene expression. In-vivo studies using stem-cell derived human astrocytes are allowing exploration of the human disease and providing insights into the neurotoxic or protective contributions of these cells to the pathogenesis of disease. The first attempts to develop astrocytic biomarkers and targeted therapies are emerging. WHERE NEXT?: Single-cell transcriptomics allows the fate of individual astrocytes to be followed in situ and provides the granularity needed to describe healthy and pathological cellular states at different stages of Alzheimer's disease. Given the differences between human and rodent astroglia, study of human cells in this way will be crucial. Although refined single-cell transcriptomic analyses of human post-mortem brains are important for documentation of pathology, they only provide snapshots of a dynamic reality. Thus, functional work studying human astrocytes generated from stem cells and exposed to pathological conditions in rodent brain or cell culture are needed to understand the role of these cells in the pathogenesis of Alzheimer's disease. These studies will lead to novel biomarkers and hopefully a series of new drug targets to tackle this disease.
Microglial control of astrocytes in response to microbial metabolites.
Rothhammer Veit,Borucki Davis M,Tjon Emily C,Takenaka Maisa C,Chao Chun-Cheih,Ardura-Fabregat Alberto,de Lima Kalil Alves,Gutiérrez-Vázquez Cristina,Hewson Patrick,Staszewski Ori,Blain Manon,Healy Luke,Neziraj Tradite,Borio Matilde,Wheeler Michael,Dragin Loic Lionel,Laplaud David A,Antel Jack,Alvarez Jorge Ivan,Prinz Marco,Quintana Francisco J
Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS). Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14 cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.
Astrocytes: Key Regulators of Neuroinflammation.
Colombo Emanuela,Farina Cinthia
Trends in immunology
Astrocytes are crucial regulators of innate and adaptive immune responses in the injured central nervous system. Depending on timing and context, astrocyte activity may exacerbate inflammatory reactions and tissue damage, or promote immunosuppression and tissue repair. Recent literature has unveiled key factors and intracellular signaling pathways that govern astrocyte behavior during neuroinflammation. Here we have re-visited in vivo studies on astrocyte signaling in neuroinflammatory models focusing on evidences obtained from the analysis of transgenic mice where distinct genes involved in ligand binding, transcriptional regulation and cell communication have been manipulated in astrocytes. The integration of in vivo observations with in vitro data clarifies precise signaling steps, highlights the crosstalk among pathways and identifies shared effector mechanisms in neuroinflammation.
Astrocyte-Secreted Glypican 4 Regulates Release of Neuronal Pentraxin 1 from Axons to Induce Functional Synapse Formation.
Farhy-Tselnicker Isabella,van Casteren Adriana C M,Lee Aletheia,Chang Veronica T,Aricescu A Radu,Allen Nicola J
The generation of precise synaptic connections between developing neurons is critical to the formation of functional neural circuits. Astrocyte-secreted glypican 4 induces formation of active excitatory synapses by recruiting AMPA glutamate receptors to the postsynaptic cell surface. We now identify the molecular mechanism of how glypican 4 exerts its effect. Glypican 4 induces release of the AMPA receptor clustering factor neuronal pentraxin 1 from presynaptic terminals by signaling through presynaptic protein tyrosine phosphatase receptor δ. Pentraxin then accumulates AMPA receptors on the postsynaptic terminal forming functional synapses. Our findings reveal a signaling pathway that regulates synaptic activity during central nervous system development and demonstrates a role for astrocytes as organizers of active synaptic connections by coordinating both pre and post synaptic neurons. As mutations in glypicans are associated with neurological disorders, such as autism and schizophrenia, this signaling cascade offers new avenues to modulate synaptic function in disease.
Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation.
Wheeler Michael A,Jaronen Merja,Covacu Ruxandra,Zandee Stephanie E J,Scalisi Giulia,Rothhammer Veit,Tjon Emily C,Chao Chun-Cheih,Kenison Jessica E,Blain Manon,Rao Vijayaraghava T S,Hewson Patrick,Barroso Andreia,Gutiérrez-Vázquez Cristina,Prat Alexandre,Antel Jack P,Hauser Russ,Quintana Francisco J
Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.
α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading.
Loria Frida,Vargas Jessica Y,Bousset Luc,Syan Sylvie,Salles Audrey,Melki Ronald,Zurzolo Chiara
Recent evidence suggests that disease progression in Parkinson's disease (PD) could occur by the spreading of α-synuclein (α-syn) aggregates between neurons. Here we studied the role of astrocytes in the intercellular transfer and fate of α-syn fibrils, using in vitro and ex vivo models. α-Syn fibrils can be transferred to neighboring cells; however, the transfer efficiency changes depending on the cell types. We found that α-syn is efficiently transferred from astrocytes to astrocytes and from neurons to astrocytes, but less efficiently from astrocytes to neurons. Interestingly, α-syn puncta are mainly found inside the lysosomal compartments of the recipient cells. However, differently from neurons, astrocytes are able to efficiently degrade fibrillar α-syn, suggesting an active role for these cells in clearing α-syn deposits. Astrocytes co-cultured with organotypic brain slices are able to take up α-syn fibrils from the slices. Altogether our data support a role for astrocytes in trapping and clearing α-syn pathological deposits in PD.
Gundersen Vidar,Storm-Mathisen Jon,Bergersen Linda Hildegard
Neuroglia, the "glue" that fills the space between neurons in the central nervous system, takes active part in nerve cell signaling. Neuroglial cells, astroglia, oligodendroglia, and microglia, are together about as numerous as neurons in the brain as a whole, and in the cerebral cortex grey matter, but the proportion varies widely among brain regions. Glial volume, however, is less than one-fifth of the tissue volume in grey matter. When stimulated by neurons or other cells, neuroglial cells release gliotransmitters by exocytosis, similar to neurotransmitter release from nerve endings, or by carrier-mediated transport or channel flux through the plasma membrane. Gliotransmitters include the common neurotransmitters glutamate and GABA, the nonstandard amino acid d-serine, the high-energy phosphate ATP, and l-lactate. The latter molecule is a "buffer" between glycolytic and oxidative metabolism as well as a signaling substance recently shown to act on specific lactate receptors in the brain. Complementing neurotransmission at a synapse, neuroglial transmission often implies diffusion of the transmitter over a longer distance and concurs with the concept of volume transmission. Transmission from glia modulates synaptic neurotransmission based on energetic and other local conditions in a volume of tissue surrounding the individual synapse. Neuroglial transmission appears to contribute significantly to brain functions such as memory, as well as to prevalent neuropathologies.
Glia as drivers of abnormal neuronal activity.
Robel Stefanie,Sontheimer Harald
Reactive astrocytes have been proposed to become incompetent bystanders in epilepsy as a result of cellular changes rendering them unable to perform important housekeeping functions. Indeed, successful surgical treatment of mesiotemporal lobe epilepsy hinges on the removal of the glial scar. New research now extends the role of astrocytes, suggesting that they may drive the disease process by impairing the inhibitory action of neuronal GABA receptors. Here we discuss studies that include hyperexcitability resulting from impaired supply of astrocytic glutamine for neuronal GABA synthesis, and epilepsy resulting from genetically induced astrogliosis or malignant transformation, both of which render the inhibitory neurotransmitter GABA excitatory. In these examples, glial cells alter the expression or function of neuronal proteins involved in excitability. Although epilepsy has traditionally been thought of as a disease caused by changes in neuronal properties exclusively, these new findings challenge us to consider the contribution of glial cells as drivers of epileptogenesis in acquired epilepsies.
Cell Biology of Astrocyte-Synapse Interactions.
Allen Nicola J,Eroglu Cagla
Astrocytes, the most abundant glial cells in the mammalian brain, are critical regulators of brain development and physiology through dynamic and often bidirectional interactions with neuronal synapses. Despite the clear importance of astrocytes for the establishment and maintenance of proper synaptic connectivity, our understanding of their role in brain function is still in its infancy. We propose that this is at least in part due to large gaps in our knowledge of the cell biology of astrocytes and the mechanisms they use to interact with synapses. In this review, we summarize some of the seminal findings that yield important insight into the cellular and molecular basis of astrocyte-neuron communication, focusing on the role of astrocytes in the development and remodeling of synapses. Furthermore, we pose some pressing questions that need to be addressed to advance our mechanistic understanding of the role of astrocytes in regulating synaptic development.
Exosome reporter mice reveal the involvement of exosomes in mediating neuron to astroglia communication in the CNS.
Men Yuqin,Yelick Julia,Jin Shijie,Tian Yang,Chiang Ming Sum R,Higashimori Haruki,Brown Eoin,Jarvis Rachel,Yang Yongjie
Astroglia play active and diverse roles in modulating neuronal/synaptic functions in the CNS. How these astroglial functions are regulated, especially by neuronal signals, remains largely unknown. Exosomes, a major type of extracellular vesicles (EVs) that originate from endosomal intraluminal vesicles (ILVs), have emerged as a new intercellular communication process. By generating cell-type-specific ILVs/exosome reporter (CD63-GFP) mice and immuno-EM/confocal image analysis, we found that neuronal CD63-GFP ILVs are primarily localized in soma and dendrites, but not in axonal terminals in vitro and in vivo. Secreted neuronal exosomes contain a subset of microRNAs (miRs) that is distinct from the miR profile of neurons. These miRs, especially the neuron-specific miR-124-3p, are potentially internalized into astrocytes. MiR-124-3p further up-regulates the predominant glutamate transporter GLT1 by suppressing GLT1-inhibiting miRs. Our findings suggest a previously undescribed neuronal exosomal miR-mediated genetic regulation of astrocyte functions, potentially opening a new frontier in understanding CNS intercellular communication.
The role of glial-specific Kir4.1 in normal and pathological states of the CNS.
Nwaobi Sinifunanya E,Cuddapah Vishnu A,Patterson Kelsey C,Randolph Anita C,Olsen Michelle L
Kir4.1 is an inwardly rectifying K(+) channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K(+) homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the potential role that Kir4.1 plays in human disease. In this article, we review the growing evidence implicating Kir4.1 in a wide array of neurological disease. Recent literature suggests Kir4.1 dysfunction facilitates neuronal hyperexcitability and may contribute to epilepsy. Genetic screens demonstrate that mutations of KCNJ10, the gene encoding Kir4.1, causes SeSAME/EAST syndrome, which is characterized by early onset seizures, compromised verbal and motor skills, profound cognitive deficits, and salt-wasting. KCNJ10 has also been linked to developmental disorders including autism. Cerebral trauma, ischemia, and inflammation are all associated with decreased astrocytic Kir4.1 current amplitude and astrocytic dysfunction. Additionally, neurodegenerative diseases such as Alzheimer disease and amyotrophic lateral sclerosis demonstrate loss of Kir4.1. This is particularly exciting in the context of Huntington disease, another neurodegenerative disorder in which restoration of Kir4.1 ameliorated motor deficits, decreased medium spiny neuron hyperexcitability, and extended survival in mouse models. Understanding the expression and regulation of Kir4.1 will be critical in determining if this channel can be exploited for therapeutic benefit.
Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism.
Hasel Philip,Dando Owen,Jiwaji Zoeb,Baxter Paul,Todd Alison C,Heron Samuel,Márkus Nóra M,McQueen Jamie,Hampton David W,Torvell Megan,Tiwari Sachin S,McKay Sean,Eraso-Pichot Abel,Zorzano Antonio,Masgrau Roser,Galea Elena,Chandran Siddharthan,Wyllie David J A,Simpson T Ian,Hardingham Giles E
The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte-neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte-neuron metabolic cooperation.
Astrocyte-Neuron Interactions in the Striatum: Insights on Identity, Form, and Function.
Khakh Baljit S
Trends in neurosciences
The physiological functions of astrocytes within neural circuits remain incompletely understood. There has been progress in this regard from recent work on striatal astrocytes, where detailed studies are emerging. In this review, findings on striatal astrocyte identity, form, and function, are summarized with a focus on how astrocytes regulate striatal neurons, circuits, and behavior. Specific features of striatal astrocytes are highlighted to illustrate how they may be specialized to regulate medium spiny neurons (MSNs) by responding to, and altering, excitation and inhibition. Further experiments should reveal additional mechanisms for astrocyte-neuron interactions in the striatum and potentially reveal insights into the functions of astrocytes in neural circuits more generally.
Adult Neurogenesis, Glia, and the Extracellular Matrix.
Cope Elise C,Gould Elizabeth
Cell stem cell
In the adult mammalian hippocampus, new neurons arise from stem and progenitor cell division, in a process known as adult neurogenesis. Adult-generated neurons are sensitive to experience and may participate in hippocampal functions, including learning and memory, anxiety and stress regulation, and social behavior. Increasing evidence emphasizes the importance of new neuron connectivity within hippocampal circuitry for understanding the impact of adult neurogenesis on brain function. In this Review, we discuss how the functional consequences of new neurons arise from the collective interactions of presynaptic and postsynaptic neurons, glial cells, and the extracellular matrix, which together form the "tetrapartite synapse."
Glia as architects of central nervous system formation and function.
Allen Nicola J,Lyons David A
Science (New York, N.Y.)
Glia constitute roughly half of the cells of the central nervous system (CNS) but were long-considered to be static bystanders to its formation and function. Here we provide an overview of how the diverse and dynamic functions of glial cells orchestrate essentially all aspects of nervous system formation and function. Radial glia, astrocytes, oligodendrocyte progenitor cells, oligodendrocytes, and microglia each influence nervous system development, from neuronal birth, migration, axon specification, and growth through circuit assembly and synaptogenesis. As neural circuits mature, distinct glia fulfill key roles in synaptic communication, plasticity, homeostasis, and network-level activity through dynamic monitoring and alteration of CNS structure and function. Continued elucidation of glial cell biology, and the dynamic interactions of neurons and glia, will enrich our understanding of nervous system formation, health, and function.
Neuron-glia interactions in the pathophysiology of epilepsy.
Patel Dipan C,Tewari Bhanu P,Chaunsali Lata,Sontheimer Harald
Nature reviews. Neuroscience
Epilepsy is a neurological disorder afflicting ~65 million people worldwide. It is caused by aberrant synchronized firing of populations of neurons primarily due to imbalance between excitatory and inhibitory neurotransmission. Hence, the historical focus of epilepsy research has been neurocentric. However, the past two decades have enjoyed an explosion of research into the role of glia in supporting and modulating neuronal activity, providing compelling evidence of glial involvement in the pathophysiology of epilepsy. The mechanisms by which glia, particularly astrocytes and microglia, may contribute to epilepsy and consequently could be harnessed therapeutically are discussed in this Review.